The neuropeptide galanin is localized in the hippocampus, coexists with acetylcholine in the rat septohippocampal pathway, coexists with norepinephrine in the locus coeruleus, and inhibits the release of glutamate, acetylcholine, and norepinephrine. Galanin is overexpressed in the basal forebrain in Alzheimer's disease. Our laboratory is engaged in investigating the behavioral concomittants of the inhibitory effects of galanin. Our past experiments revealed that galanin administration to rats impairs performance on several learning and memory tasks. Last year, our galanin research program focused on a new research tool. Galanin overexpressing transgenic mice generated on a dopamine beta hydroxylase promoter by Robert Steiner and coworkers at the University of Washington, Seattle were evaluated for behavioral phenotype. The chimera line was backcrossed for 7 generations into a C57BL/6J background and bred at The Jackson Laboratory for our behavioral experiments. Postdoctoral fellow Andrew Holmes and several student volunteers completed the first behavioral phenotyping on galanin transgenic mice (GAL-tg) and their wild type control littermates (WT). General health, home cage behaviors, neurological reflexes, and motor functions were normal. Dr. Holmes discovered impaired performance on the Morris water task in the GAL-tg at ages 8, 16, and 24 months. The profile of the behavioral deficits was similar to that seen in rats given exogenous galanin. Normal performance on the visible and hidden platform components was followed by lack of selective search on the probe trial. Postdoctoral fellow Jeff Kinney replicated these findings in a separate group of GAL-tg and WT mice. Dr. Holmes analyzed the probe trial deficit further. No genotype differences were detected on swim speed, thigmotaxis, or sequence of swim pattern across ten second time bins in the probe trial. These findings indicate that the GAL-tg mutation produces a selective deficit in the ability of mice to generate a cognitive map based on distal spatial cues. Postdoctoral fellow Craige Wrenn tested the galanin transgenic mice on a second memory task, social transmission of food preference. Wild type littermate control mice showed the expected preference for a food scented with a flavor previously consumed by a cagemate 24 hours earlier. GAL-tg did not show a preference for consuming the food containing the socially transmitter odor cue, as compared to consumption of food containing a novel odor. Dr. Wrenn replicated this finding in a separate group of GAL-tg and WT mice. Dr. Wrenn completed several critical control experiments, demonstrating that GAL-tg engaged in normal levels of social interaction with the demonstrator cagemate, and displayed normal olfactory abilities. Dr. Kinney tested the galanin transgenic mice on a third memory task, cued and contextual fear conditioning. GAL-tg were not significantly different than WT on freezing to the identical context in which an aversive stimulus had been presented, nor on freezing to an auditory cue previously paired with the aversive stimulus but presented in a new context. Dr. Kinney then employed the trace fear conditioning modification. The emotional learning task was made more difficult by the insertion of a delay between the aversive unconditioned stimulus and the auditory cue during training. GAL-tg showed poor performance on auditory cued freezing in the trace fear conditioning task. Dr. Kinney conducted critical control experiments that indicated normal analgesic responses and normal hearing in the GAL-tg. Poor performance by the galanin transgenics on the probe trial of the Morris spatial navigation task, on the social transmision of food preference olfactory task, and on the trace fear conditioning emtional memory task, confirm a cognitive deficit in the galanin overexpressing mice. Corroboration across three diverse learning and memory tasks, representing highly divergent sensory and motor demands, supports the interpretation of a generalized cognitive disorder in GAL-tg mice. Our findings indicate that more challenging memory tasks are more sensitive to galanin overexpression in mice. These results are consistent with the current theory that neuropeptides are neuromodulators released under conditions of high neuronal firing, that convey highly selective information to postsynaptic neurons. Cognitive deficits in galanin overexpressing mice may be relevant to cognitive deficits in galanin overexpressing patients suffering from Alzheimer's disease.